{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:24:09Z","timestamp":1792679049055,"version":"4.5.0"},"reference-count":74,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T00:00:00Z","timestamp":1659484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We queried the Florida Autopsied Multi\u2010Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non\u2010AD neuropathologies and tauopathies. Thioflavin\u2010S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n\u00a0=\u00a024 cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin\u2010S. Hippocampal burden generally increased with each Braak stage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline\u2010rich region.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Novel semi\u2010quantitative frequency to calculate tangle maturity frequency.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.12749","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T08:15:10Z","timestamp":1659514510000},"page":"1029-1040","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Phosphorylated tau sites that are elevated in Alzheimer's disease fluid biomarkers are visualized in early neurofibrillary tangle maturity levels in the\n                    <i>post mortem<\/i>\n                    brain"],"prefix":"10.1002","volume":"19","author":[{"given":"Christina M.","family":"Moloney","sequence":"first","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney A.","family":"Labuzan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia E.","family":"Crook","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habeeba","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Quantitative 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neill R.","family":"Graff\u2010Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Mielke","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"},{"name":"Division of Epidemiology Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7379-2545","authenticated-orcid":false,"given":"Melissa E.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Neuroscience 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